1. Field of the Invention
The invention relates to methods and pharmaceutical compositions used to treat chronic progressive vascular diseases.
2. Description of the Prior Art
Chronic progressive vascular disease (CPVD) is a complication of several of the most common diseases afflicting the developed world, including diabetes mellitus, hypertension, the various hyperlipidemias, and the like. The present therapeutic modalities dealing with CPVD are aimed at the underlying causes. Unfortunately, for the most part there are no known cures, or their control is very difficult to accomplish in the general population. In addition, CPVD is often not only well-established, but also far-advanced, by the time that the underlying cause(s) come to medical attention. Thus, one is left with attempting to treat secondary complications, of which CPVD is the most serious because it leads to renal failure, strokes, heart disease and blindness.
Generally, CPVD is characterized by a change in vascular smooth muscle cells. One of the major changes is an increase in the amount and alteration of the types of connective tissue that they synthesize. This results in scarring and marked changes in function. In blood vessels, this leads to loss of elasticity, resulting in vessels which do not distend and contract and which have thickened walls and narrowed lumens. The end result is reduced blood flow or complete blockage. Examples of vascular diseases characterized by these pathophysiological processes include chronic progressive glomerular disease, e.g., diabetic-induced glomerulosclerosis (scarring); progressive renal failure after renal transplantation; occlusion of shunts used to provide vascular access in patents with endstage renal disease being treated with hemodialysis; other chronic small blood vessel diseases (such as in some patients with hypertension); recurrence of stenosis in patients who have undergone coronary bypass surgery; and diabetic retinopathy.
The therapeutic goal of any treatment for CPVD must be to decrease the already-formed excess of extracellular matrix (scarring) in order to restore normal vessel patency and function. However, there is currently no direct method of interfering with abnormalities in smooth muscle tissue metabolism or to modulate connective tissue synthesis, despite their importance in chronic progressive disease. Progression of these diseases has been considered to be both inevitable and irreversible.
Heparin and some of its analogs have been found to inhibit smooth muscle proliferation (see, e.g., Castellot et al., J. Cell. Biol., 102: 1979-1984, 1986). However, these findings have only been applied to the prevention of vascular diseases, generally through parenteral administration, but not to the treatment and reversal of established lesions. Since less than 50% of patients at risk develop CPVD and it is not possible to predict precisely who will develop these diseases, nor how rapidly they will progress, a preventative therapeutic strategy is impractical. Furthermore, daily injections are not acceptable to most patients for the delivery of other than life-saving medications (such as insulin). It is therefore particularly important that a treatment regimen be developed for CPVD, preferably involving oral administration of a pharmaceutical agent of low toxicity, which is effacious in treating and reversing CPVD by causing regression and degradation of established lesions.
Pentosan polysulfate (PPS) is a highly sulfated, semi-synthetic polysaccharide with a molecular weight ranging from about 1,500 to 6,000 Daltons, depending on the mode of isolation. PPS may be in the same general class as heparins and heparinoids, but there are a number of differences in chemical structure, methods of derivation and physico-chemical properties between PPS and heparin. While heparin is usually isolated from mammalian tissues such as beef and pork muscles, liver and intestines, PPS is a semi-synthetic compound whose polysaccharide backbone, xylan, is extracted from the bark of the beech tree or other plant sources and then treated with sulfating agents such as chlorosulfonic acid or sulfuryl trichloride and acid. After sulfation, PPS is usually treated with sodium hydroxide to yield the sodium salt.
As illustrated by the following formulas, ##STR1## heparin is a sulfated polymer of repeating double sugar monomers, (D)-glucosamine and (D)-glucuronic acid (both 6-carbon hexose sugars), with an amine function on the glucosamine; PPS is a sulfated linear polymer of repeating single monomers of(D)-xylose, a 5-carbon pentose sugar in its pyranose ring form. While heparin rotates plane polarized light in a dextrorotatory direction, PPS rotates light in a levorotatory direction.
In terms of biological properties, PPS prolongs partial thromboplastin time and has been used to prevent deep venous thrombosis, but it has only about one-fifteenth the anticoagulant potency of heparin (see generally Wardle, J. Int. Med. Res., 20:361-370, 1992). PPS has also been disclosed as useful in the treatment of urinary tract infections and interstitial cystitis (U.S. Pat. No. 5,180,715) and, in combination with an angiostatic steroid, in arresting angiogenesis and capillary, cell or membrane leakage (U.S. Pat. No. 4,820,693).
Some researchers have demonstrated that PPS inhibits smooth muscle cell proliferation and decreases hyperlipidemia, and on that basis have suggested that PPS might be useful prophylactically in limiting atherosclerotic plaque formation, inhibiting mesangial cell proliferation and preventing collagen formation and glomerulosclerosis (Paul et al., Thromb. Res., 46:793-801, 1987; Wardle, ibid.). However, no one had previously considered that it was feasible to reverse vascular scarring, i.e., PPS had not been considered in this context.